Harry Fowler

Shock-induced modulation of lymphocyte reactivity: suppression, habituation, and recovery

The present study was designed to evaluate the suppressive effect of different frequencies of signaled-shock presentations on mitogenic reactivity of lymphocytes in Lewis rats, and to assess the recovery of that reactivity at varying times after the shocks. The results showed that the magnitude of decreased reactivity in both the spleen and whole-blood lymphocytes, as determined by mitogenic reactivity to Concanavalin A (Con A), was directly related to the number of shock presentations within a daily session. However, the suppressed reactivity for the spleen cells diminished with repeated sessions of frequent shocks, in contrast to the whole-blood lymphocytes which did not show any habituation. Furthermore, the imposition of different periods of recovery following a single session of frequent shocks showed that the decreased reactivity for the whole-blood lymphocytes extended beyond the immediate period of the shock experience, and took 48 to 96 hours to recover completely. In contrast, the spleen lymphocytes showed complete recovery within 24 hours following the administration of shock. These results establish that the rate of habituation to and recovery from a shock-induced decrease in mitogen reactivity is more rapid for the spleen than whole-blood lymphocytes.

Pavlovian conditioning of shock-induced supression of lymphocyte reactivity: Acquisition, extinction, and preexposure effects

Recent research has indicated that physical stressors, such as electric shock, can suppress immune function in rats. The present study investigated whether a nonaversive stimulus that had been associated with electric shock would also impair immune function. Presentation of that conditioned stimulus (CS) by itself produced a pronounced suppression of lymphocyte proliferation in response to the nonspecific mitogens, Concanavalin-A (ConA) and Phytohemagglutinin (PHA). In further evidence of a conditioning effect, the suppression was attenuated by extinction and preexposure manipulations that degraded the associative value of the CS. These results indicate that a psychological or learned stressor can suppress immune reactivity independently of the direct effect of physically aversive stimulation or of ancillary changes in dietary and health-related habits.

The effects of lithium on a potential cycling model of bipolar disorder

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

Effects of contingency violations on the extinction of a conditioned fear inhibitor and a conditioned fear excitor.

Rats were used in a conditioned-suppression paradigm to assess the effects of contingency variations on responding to a conditioned inhibitor (CS-) and a conditioned excitor (CS+). In Experiment 1, various unconditioned stimulus (US) frequencies were equated across the presence and absence of a CS- in the context of either background cues (continuous-trial procedure) or an explicit neutral event (discrete-trial procedure). With both procedures, a CS-alone treatment enhanced inhibition, whereas treatments involving 50% or 100% reinforcement for the CS- eliminated inhibition without conditioning excitation to that CS. The latter outcome also occurred in Experiment 2, with discrete-trial training equating considerably reduced US frequencies for the presence and absence of the CS-. In further evidence that inhibition was eliminated without conditioning excitation to the CS-, Experiment 3 showed that a novel CS did not acquire excitation when 25%, 50%, or 100% reinforcement was equated across the presence and absence of that CS in the context of a discrete-trial event. Using the procedures of Experiment 1, Experiment 4 showed that a CS+ was extinguished by a CS-alone treatment but was substantially maintained by treatments involving 50% or 100% uncorrelated reinforcement. These effects for a CS+ and a CS- implicate CS-US contiguity, rather than contingency, as the factor determining the extinction of a CS.

Suppression and Facilitation by Response Contingent Shock

Publisher Summary This chapter discusses different functions of the punishment procedure and focuses on a “reverse” strategy. It also focuses on the extent to which the suppression produced by punishment is indicative of a suppression function. The chapter then describes the varied functions of punishment and presents a comparison of these functions with those of a non-aversive stimulus contingency, such as where the procedural operation for punishment is met through the use of a “neutral” rather than a noxious stimulus. It also highlights paradoxical effects of punishment that show facilitated performance where a suppression effect is clearly expected. The chapter further focuses on those circumstances where such facilitation is produced by response-contingent electric shock. It also focuses on shock as a punishing stimulus. The chapter describes the functions of punishment that may be reflected by paradoxical facilitation. There are two broad and arbitrary classes of the study of paradoxical effects: the first bearing on the possible stimulus or “cue” functions of punishment and the second relating to the response-eliciting functions of punishment. This classification is representative of a treatment in which punishment is viewed primarily with respect to its effects as a stimulus—firstly as conditioned stimulus and secondly as an unconditioned stimulus or response elicitor.

Enhancement of Conditioned Inhibition via an Extinction Treatment

Rats were used in a conditioned-suppression paradigm to determine whether an extinction treatment would enhance a moderately developed conditioned inhibitor (CS−). To dissipate unconditioned suppression to the training stimuli, the subjects were first habituated to the stimuli and then given Pavlovian conditioned-inhibition (CI) training involving reinforced presentations of a clicker and nonreinforced compound presentations of that stimulus and the intended CS−, either a light or a tone. Thereafter, experimental subjects received presentations of their CS− by itself, whereas controls received no further training. Following the occurrence and loss of conditioned suppression to the CS− in the extinction phase, summation and retardation tests showed enhanced CI for the experimental subjects relative to both the controls and their own earlier levels of inhibitory performance. In fact, the enhanced inhibition for the experimental subjects approximated that shown by a comparison group for which the CS− had been strongly developed as an inhibitor. These findings suggest that an excitatory representation is associated with the CS− early in CI training, and that subsequent presentations of the CS− by itself strengthen its inhibitory effect by allowing it to be nonreinforced in the presence of that representation.

Satiation and Curiosity: Constructs for a Drive and Incentive-Motivational Theory of Exploration1

Publisher Summary This chapter discusses nature of exploration, its relation to early motivational interpretations, and the manner in which these interpretations may be successfully accommodated within a drive and incentive-motivational theory. The concept of an exploratory drive obtains tentative operational expression in the length and constancy of the animals exposure to an impinging stimulus condition, or conversely, with the animals “deprivation” of a change in stimulation. Correspondingly, the magnitude of the incentive or reinforcement involved in the learning of instrumental behaviors may be related to the magnitude of the change in stimulation that is provided by the relatively novel or unfamiliar stimuli to and for which the animal responds. The problem of delineating exploratory phenomena might be viewed with respect to a resolution on the basis of a presumed effect of exploration, that is, the commonly held position that exploratory behaviors have the prime function of altering those stimuli currently impinging upon the organism. Thus, exploration as a label may be relegated to those behaviors that are instrumental to the animals receipt of relatively novel or changed stimuli.

Characterization of immune alterations induced by a conditioned aversive stimulus

In this study, we investigated the immune alterations induced in rats by an aversive conditioned stimulus that had been developed through pairings with electric shock. The results showed that the conditioned stimulus induced a pronounced suppression of the mitogenic responsiveness of splenic and blood lymphocytes and a reduction in splenic natural killer cell activity. In contrast, the conditioned stimulus did not induce any alteration in the mitogenic responsiveness of lymphocytes from the mesenteric lymph nodes. The reduction in the mitogenic responsiveness of splenic lymphocytes was not related to a reduction in the level of interleukin-2 (IL-2) production, as splenic lymphocytes from subjects exposed to the conditioned stimulus showed normal levels of IL-2. Plasma corticosterone measurements showed that glucocorticoid secretion was related to the alteration of the mitogenic responsiveness of blood lymphocytes. However, plasma corticosterone levels were not related to any of the other immune measures. These findings establish that a signal for an aversive event can have a pronounced effect on immune function, but that such an effect is dependent on the particular compartment of the immune system studied. These results support the claim that glucocorticoids can induce immune alterations, but they suggest that additional pathways must be involved in the immune alterations induced by a conditioned aversive stimulus.

Signaling and affective functions in Pavlovian conditioning

The present study employed a Pavlovian-instrumental-transfer paradigm to investigate the role of conditioned fear in appetitive discrimination learning. Each of three Pavlovian training procedures was used to establish a conditioned fear excitor (CS+), a “neutral” CS (CSo), and a conditioned fear inhibitor (CS−). Then, the CSs were administered to rats in the three groups contingent upon the rewarded response in a difficult visual discrimination. In addition, half of each group received shock punishment for each incorrect response. Relative to CSo, CS+ facilitated performance in contrast to the usual interfering effect of conditioned suppressors; conversely, CS− retarded performance even when its reinforcing action (fear inhibition) was potentiated by punishment for the incorrect response. These results, together with other findings showing a reversed outcome when the CSs are administered for the incorrect response, indicate that Pavlovian conditioning comprises both general signaling and affective functions, the former reflecting a basic “expectancy” or nominal type of cognitive processing in the rat.

Oscellatory-sensitization model of repeated drug exposure: Cocaine's effects on shock-induced hypoalgesia

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.